The overall objective of this project is to evaluate the risk of urban (epidemic) yellow fever (YF) reappearing in the Americas. Because of increasing urbanization, the abundance of the urban mosquito vector (Aedes aegypti) in most Neotropical cities, decreasing vaccine coverage, rapid transportation, and the unprecedented level of human activity in jungle areas where YF virus is endemic, there is now major concern that the epidemic or urban form of the disease will reappear in the Americas. We have recently developed a hamster model of YF, which mimics the clinical and pathological manifestations observed in severe forms of the disease in humans and monkeys. Using the hamster model, an attempt will be made to validate several of the hypotheses of why urban YF is currently absent from the Americas. There are four specific aims, which will test the hypotheses and will examine various aspects of the epidemiology of YF in the New World. These involve comparative studies of the virulence for hamsters and the infectivity for Ae.aegypti of the four major genotypes of YF virus; an investigation of the role of pre-existing heterologous flavivirus antibodies in modifying the severity of YF; and an evaluation of the importance of vertical (transovarial) virus transmission in two New World sylvan vectors (Haemagogus janthinomys and Sabethes chioropterus) in maintenance of the enzootic forest cycle. The project involves the disciplines of virology, tropical medicine, pathology, medical entomology and public health. Most of the work will be done in laboratories at the University of Texas Medical Branch, Center for Tropical Diseases; but a small portion will be done at the Evandro Chagas Institute in Belem, Brazil.